Studies of P-glycoprotein Drug Interactions - Administrative Supplement for Undergraduate Summer Research
P-糖蛋白药物相互作用的研究 - 本科生暑期研究行政补充
基本信息
- 批准号:10810072
- 负责人:
- 金额:$ 0.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:ABCB1 geneATP HydrolysisATP-Binding Cassette TransportersAccelerationAdministrative SupplementAffinityAmberAmino AcidsAntineoplastic AgentsAreaAromatic Amino AcidsBindingBinding SitesBiochemicalBiologicalBiological AssayBiological AvailabilityBiomedical EngineeringBlood - brain barrier anatomyCardiovascular AgentsCardiovascular systemCell membraneCellsChemicalsClinicalCodon NucleotidesCryoelectron MicroscopyCytoplasmCytoplasmic TailDevelopmentDimerizationDiseaseDocumentationDrug Binding SiteDrug CombinationsDrug DesignDrug EffluxDrug InteractionsDrug KineticsDrug Metabolic DetoxicationDrug MonitoringDrug TransportDrug resistanceDrug usageEnergy TransferEngineeringEnvironmentExcretory functionFluorescenceFluorescence SpectroscopyFluorescent ProbesFundingGoalsHIV/AIDSHydrophobicityIntestinesKidneyKineticsKnowledgeLaboratoriesLearningLigand BindingLipid BilayersLiverMapsMeasuresMembraneMental disordersMolecularMolecular ConformationMonitorMulti-Drug ResistanceNifedipineNucleotidesPaclitaxelPharmaceutical PreparationsPositioning AttributePrazosinPropertyPumpRecombinant ProteinsRhodamine 123Roentgen RaysScientistScreening procedureSiteStructureSurfaceSystemTechnologyTerminator CodonTertiary Protein StructureTestingTherapeuticToxinTransmembrane DomainTryptophanUnited States Food and Drug AdministrationVariantVinblastineX-Ray Crystallographyabsorptionbiophysical techniquescancer drug resistancecancer therapyclinically relevantcombatefflux pumpexperienceexperimental studyfunctional groupinhibitorinsightmolecular pumpnanodisknovel strategiesnovel therapeuticspreventprotein purificationprotein reconstitutionrational designreconstitutionsingle moleculesuccesssummer researchtooltryptophan analogundergraduate studentuptake
项目摘要
PROJECT SUMMARY/ABSTRACT (of the original funded project)
P-glycoprotein (Pgp) is a molecular pump that detoxifies cells by transporting hundreds of structurally unrelated
toxins out of the cell. Pgp limits uptake in the intestines, and enhances excretion of drugs in the liver, kidney and
blood-brain barrier, of many drugs that are used for treatment of cancers, HIV/AIDS, psychiatric illnesses, and
cardiovascular conditions. It is among the seven most important transporters responsible for regulating drug
absorption and disposition that now require documentation of drug interactions for approval of any new drugs by
the US Food and Drug Administration (FDA). Pgp is an ATP-binding cassette transporter with two
transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs). It uses ATP hydrolysis to pump
substrates across the cell membranes. Our recent X-ray structures of Pgp identified hydrophobic and aromatic
amino acids that contribute to binding of different inhibitors to the drug-binding site. In this proposal, we will test
the hypothesis that therapeutic drugs bind to different subsets of residues within defined subpockets in the TMDs
of the protein. Our general approach is to introduce tryptophans (Trps) at strategic positions in order to monitor
drug binding. The Trps will be introduced on the background of a new fully functional Trp-less Pgp, or a low-Trp
Pgp that retains three native conformationally sensitive Trps in the cytoplasmic domains. Using fluorescence
changes, such as quenching, and resonance energy transfer (FRET), we will map out sites of interaction of the
purified protein with prototypical substrates that occupy biochemically defined and distinct binding sites, as well
as those of common therapeutic drugs and newly identified inhibitors. We will further insert a fluorescent Trp
analog (L-Anap) into wild-type Pgp using the amber stop codon suppression strategy to explore monitoring drug
binding in biological cell membranes. By determining how drugs and inhibitors modulate the cooperativity and
conformational dynamics of this multidomain transporter, we will gain unique insight into the mechanisms of drug
binding and their effects on Pgp function. With these new approaches, we will address the molecular mechanism
and kinetics of drug/inhibitor binding, determine synergistic effects, and refine the mechanisms of drug-drug
interactions in Pgp. The information will pave the way to new analytical approaches to refine Pgp drug interaction
studies of old and new drugs, and will be invaluable to redesign drugs with clinically favorable pharmacokinetics
and accelerate pharmacotherapeutic developments.
(原资助项目的)项目摘要/摘要
P-糖蛋白(Pgp)是一种分子泵,通过转运数百种结构上无关的
毒素从细胞中排出。PGP限制了肠道的摄取,并促进了药物在肝脏、肾脏和
血脑屏障,许多用于治疗癌症、艾滋病毒/艾滋病、精神疾病和
心血管疾病。它是负责监管药物的七个最重要的转运体之一
吸收和处置现在需要药物相互作用的文件,以批准任何新药
美国食品和药物管理局(FDA)。PGP是一种三磷酸腺苷结合盒运输器,有两个
跨膜结构域(TMD)和两个核苷酸结合结构域(NBD)。它用三磷酸腺苷水解液来泵送
底物穿过细胞膜。我们最新的PGP的X射线结构确定了疏水性和芳香性
有助于不同抑制剂与药物结合部位结合的氨基酸。在这份提案中,我们将测试
治疗药物与TMD中不同亚组残留物结合的假说
蛋白质的含量。我们的一般方法是在战略位置引入色氨酸(Trp),以便监测
药物捆绑。TRP将在新的全功能无TRP PGP或低TRP的背景下推出
在细胞质结构域中保留三个天然构象敏感的TRPs的PGP。使用荧光法
变化,如猝灭,和共振能量转移(FRET),我们将绘制出相互作用的位置
具有具有生物化学定义的不同结合部位的原型底物的纯化蛋白
与常见的治疗药物和新发现的抑制剂一样。我们将进一步插入一个荧光色氨酸
类似物(L-ANAP)导入野生型Pgp利用琥珀终止密码子抑制策略探讨药物监测
结合在生物细胞膜上。通过确定药物和抑制剂如何调节协作性和
这种多结构域转运蛋白的构象动力学,我们将对药物的作用机制有独特的见解
结合及其对PgP功能的影响。通过这些新的方法,我们将解决分子机制
和药物/抑制剂结合的动力学,确定协同效应,提炼药物-药物的作用机制
PGP中的相互作用。这些信息将为改进PGP药物相互作用的新分析方法铺平道路
对新旧药物的研究,对于重新设计具有良好临床药代动力学的药物将是非常有价值的
并加快药物治疗的发展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('INA L URBATSCH', 18)}}的其他基金
Studies of P-glycoprotein Drug Interactions - Administrative Supplement for Equipment Purchase
P-糖蛋白药物相互作用研究-设备采购行政补充
- 批准号:
10795338 - 财政年份:2022
- 资助金额:
$ 0.75万 - 项目类别:
Understanding polyspecific drug binding in P-glycoprotein
了解 P-糖蛋白中的多特异性药物结合
- 批准号:
8365444 - 财政年份:2012
- 资助金额:
$ 0.75万 - 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
- 批准号:
8152921 - 财政年份:2010
- 资助金额:
$ 0.75万 - 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
- 批准号:
8715824 - 财政年份:
- 资助金额:
$ 0.75万 - 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
- 批准号:
8306892 - 财政年份:
- 资助金额:
$ 0.75万 - 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
- 批准号:
8534191 - 财政年份:
- 资助金额:
$ 0.75万 - 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
- 批准号:
8379742 - 财政年份:
- 资助金额:
$ 0.75万 - 项目类别:
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